Methods of treatment using a gastric retained gabapentin dosage

ABSTRACT

A method of treatment for epilepsy and other disease states is described, which comprises the delivery of gabapentin in a gastric retained dosage form.

BACKGROUND OF THE INVENTION

1. Technical Field

The present invention relates to the use of gabapentin in a gastricretained dosage form. More specifically, the invention relates to theuse of such dosage form to treat epilepsy and other disease states.

2. Background

Gabapentin (1-(aminomethyl)cyclohexaneacetic acid) is an anti-epilepticdrug that is currently available in 100 mg, 300 mg and 400 mg hard shellcapsule as well as 600 mg and 800 mg tablet dosage forms, withrecommended dosing of 900 mg to 1800 mg total daily dose in threedivided dosages. The oral bioavailability is dose-dependent, withapproximately 60% bioavailability for a dose in the range of 300-400 mg,but with only 35% bioavailability for a dose of 1600 mg (Bourgeois,Epilepsia 36 (Suppl. 5):S1-S7 (1995); Gram, Epilepsia 37 (Suppl.6):S12-S16 (1996)). The decrease in bioavailability with dose has beenattributed to carrier-mediated absorption (Stewart, et al.,Pharmaceutical Research 10(2):276-281 (1993).

In early work with rats, Vollmer, et al., Arzneim-Forsch/Drug Research36(1, Nr. 5):781-892 (1986) found that the absorption site forgabapentin was the duodenum. The absorption of gabapentin occursrelatively slowly with the peak plasma concentration occurringapproximately 2-6 hours after dosing (Bourgeois, supra). The eliminationof gabapentin is exclusively through renal pathways (Chadwick; TheLancet 343:89-91 (1994); Vollmer, supra; Thomson, et al., Clin.Pharmacokinet. 23(3):216-230 (1992); and Riva, et al., Clin.Pharmacokinet. 31(6):470-493 (1996)) with reported half-lives of 5-7hours (Chadwick, supra) and 6-7 hours (Gram, supra).

A once- or twice-daily dosage form of gabapentin would be expected toimprove compliance and therefore a controlled release dosage form hassome distinct advantages over the conventional immediate releaseformulations. In addition, a controlled release dosage form would lowerthe maximum plasma concentration, and this may result in reduced sideeffects. Since gabapentin is absorbed high in the gastrointestinaltract, by means of a saturable transport mechanism, a gastric retaineddosage form is particularly beneficial for delivery of gabapentin sincethe dosage form would be able to keep the drug in the region ofabsorption and show improved bioavailability by virtue of the slowerrelease rate that avoids saturation of the carrier mediated transport ofconventional dosages.

SUMMARY OF THE INVENTION

One aspect of the invention relates to a method of treating epilepsycomprising administering a therapeutically effective amount ofgabapentin or a pharmaceutically acceptable salt thereof, in a gastricretained dosage form to a mammal in need of such treatment.

Yet another aspect of the invention relates to a method of treatingneuropathic pain comprising administering a therapeutically effectiveamount of gabapentin or a pharmaceutically acceptable salt thereof, in agastric retained dosage form to a mammal in need of such treatment.

Still another aspect of the invention relates to an improved method ofadministering a therapeutically effective amount of gabapentin to apatient in need thereof, the improvement comprising administeringgabapentin or a pharmaceutically acceptable salt thereof, in a gastricretained dosage form.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the dissolution profiles for three GR™ formulations;and

FIG. 2 illustrates the average plasma profile of three GR™ formulationsand Nuerontin.

DESCRIPTION OF THE INVENTION

The invention relates to a method of treating a disease state, such asepilepsy, by administering gabapentin in a once- or twice-daily gastricretained dosage form. The gastric retained dosage form is particularlybeneficial for delivery of gabapentin due to its prolonged transit inthe upper gastrointestinal tract, which allows the drug to be absorbedadequately in the preferred region of absorption. In addition, a gastricretained dosage form increases the t_(max) and allows for a smoother,more prolonged anti-spasmolytic effect. This dosage form also lowers theC_(max) and may result in reduced incidence and/or severity of CNS sideeffects of the drug, such as somnolence, ataxia, fatigue and dizziness.

Method of Treatment

The instant invention is a method of treating a disease state comprisingadministering a therapeutically effective amount of gabapentin, or apharmaceutically acceptable salt thereof, once- or twice-daily in agastric retained dosage form to a mammal in need of such treatment. Asused herein, the term “treating” covers treating the specified diseasein a mammal, particularly a human, and includes:

-   -   (i) preventing the disease from occurring in a subject which may        be predisposed to the disease but has not yet been diagnosed as        having it;    -   (ii) inhibiting the disease, i.e. arresting its development; or    -   (iii) relieving the disease, i.e. causing regression of the        disease.

One embodiment of the invention relates to an improved method ofadministering a therapeutically effective amount of gabapentin to apatient in need thereof, the improvement comprising administeringgabapentin or a pharmaceutically acceptable salt thereof, in a gastricretained dosage form.

Other embodiments of the invention relate to methods of treatingspecific disease states comprising administering a therapeuticallyeffective amount of gabapentin or a pharmaceutically acceptable saltthereof, in a gastric retained dosage form to a mammal in need of suchtreatment. Such methods find utility in treating numerous disease statesthat are currently being treated with conventional immediate releaseformulations of gabapentin and include, by way of illustration and notlimitation, epilepsy; neuropathic pain; psychiatric disorders such asbipolar disorder and panic disorder; movement disorders such as restlessleg syndrome, periodic movement disorder of sleep, essential tremor andacquired nystagmus; and prophylaxis of migraine headaches.

The invention also contemplates administering one or more additionaltherapeutic agents with the gabapentin treatment. The selection of theseadditional therapeutic agents will depend upon the specific diseasestate being treated, and are described in detail below.

Active Ingredient

The active ingredient in the method of the invention is gabapentin.Gabapentin is preferably used in the free amphoteric form.Pharmaceutically acceptable salt forms that retain the biologicaleffectiveness and properties of gabapentin and are not biologically orotherwise undesirable can also be used and may show superiorbioavailability. As used herein, the term “gabapentin” is intended toinclude the agent itself, as well as its pharmaceutically acceptablesalts.

Pharmaceutically acceptable salts may be amphoteric and may be presentin the form of internal salts. Gabapentin may form acid addition saltsand salts with bases. Exemplary acids that can be used to form suchsalts include, by way of example and not limitation, mineral acids suchas hydrochloric, hydrobromic, sulfuric or phosphoric acid or organicacids such as organic sulfonic acids and organic carboxylic acids. Saltsformed with inorganic bases include, for example, the sodium, potassium,lithium, ammonium, calcium, and magnesium salts. Salts derived fromorganic bases include, for example, the salts of primary, secondary andtertiary amines, substituted amines including naturally-occurringsubstituted amines, and cyclic amines, including isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethyl aminoethanol, tromethamine, lysine, arginine,histidine, caffeine, procaine, hydrabamine, choline, betaine,ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, fumarate, maleate, succinate,acetate and oxalate.

Additional Therapeutic Agents

The methods of the invention also contemplate the addition of one ormore therapeutic agents with the gabapentin treatment.

For those embodiments of the invention where the gabapentin gastricretained dosage form is administered to treat epilepsy, such additionaltherapeutic agents can be other anti-epileptics or anticonvulsants,which include, by way of illustration and not limitation, hydantoins,iminostilbenes, valproates, phenyltriazines, barbiturates,deoxybarbiturates, benzodiazepines and carbamates. Such additionalagents are preferably hydantoins, iminostilbenes, valproates orphenyltriazines.

The following examples of compounds within each of these classes isintended to be illustrative and not limiting in any manner. Examples ofsuitable hydantoin anticonvulsants include ethotoin, fosphenytoin,mephenytoin, and, preferably, phenytoin. An examples of a suitableiminostilbene is carbamazepine. Examples of suitable valproates includevalprioic acid and sodium valproate. An exemplary suitablephenyltriazine is lamotrigene. A suitable barbiturate is phenobarbitaland an exemplary deoxybarbiturate is primidone. An example of a suitablebenzodiazepine is clorazepate. A suitable carbamate is felbamate.

For those embodiments of the invention where the gabapentin gastricretained dosage form is administered to treat neuropathic pain, suchadditional therapeutic agents can be selected from the group consistingof other anticonvulsants, tricyclic antidepressants, levadopa, andopioids.

The following examples of compounds within each of these classes isintended to be illustrative and not limiting in any manner. Examples ofsuitable anticonvulsants include carbamazepine, phenytoin andlamotrigine. Suitable tricyclic antidepressants include amitriptyline,imipramine, clomipramine and desipramine. Examples of suitable opioidsinclude oxycodone and tramadol.

For those embodiments of the invention where the gabapentin gastricretained dosage form is administered to treat psychiatric disorders,such additional therapeutic agents can be selected from the groupconsisting of lithium, carbamazepine, valproate, trifluoperazine,clonazepam, risperidone, lorazepam, venlafaxine, clozapine, olanzapine,benzodiazepines, neuroleptics, tricyclic antidepressants, selectiveserontin reuptake inhibitor (SSRI's), buprupion, and nefadone.

For those embodiments of the invention where the gabapentin gastricretained dosage form is administered to treat bipolar disorder, suchadditional therapeutic agents can be selected from the group consistingof lithium, carbamazepine, valproate, trifluoperazine, clonazepam,risperidone, lorazepam, venlafaxine, clozapine, olanzapine,benzodiazepines, and neuroleptics.

For those embodiments of the invention where the gabapentin gastricretained dosage form is administered to treat depression, suchadditional therapeutic agents can be selected from the group consistingof tri-cyclic anti-depressants, SSRI's, bupropion, venlaxatine, andnefadone.

For those embodiments of the invention where the gabapentin gastricretained dosage form is administered to treat manic disorders, suchadditional therapeutic agents can be selected from the group consistingof diazepam, and oxazepam.

For those embodiments of the invention where the gabapentin gastricretained dosage form is administered to treat movement disorders, suchadditional therapeutic agents can be selected from the group consistingof benzodiazepines, dopaminergic agents, and opiates, particularlylevodopa/carbidopa and clonazepam.

For those embodiments of the invention where the gabapentin gastricretained dosage form is administered for prophylactic treatment ofmigraine headaches, such additional therapeutic agents can be selectedfrom the group consisting of tricyclic antidepressants (amitriptyline,doxepin, imipramine, maprotiline, protriptyline, desipramine), SSRI(fluoxetine), triptine (sumatriptan, etc.), and ergotamine.

Dosage

In general, the term “therapeutically effective amount” refers to thatamount which is sufficient to effect treatment, when administered to amammal in need of such treatment. The therapeutically effective amountwill vary depending on the subject being treated, the severity of thedisease state and the manner of administration, and may be determinedroutinely by one of ordinary skill in the art.

In particular, for use in the treatment of epilepsy or neuropathic painwith a gastric retained dosage form, gabapentin may be used at dosesappropriate for treating epilepsy or neuropathic pain with immediaterelease dosage forms. However, the gastric retained dosage form isdesigned to provide for bioavailability of gabapentin at a level greaterthan or equal to 80% (>80%) relative to an equal dose of an immediaterelease dosage form. Typically, the method of the invention will involveadministering gabapentin on a once- or twice-daily basis for as long asthe condition persists.

An effective dosage of gabapentin for the treatment of epilepsy istypically in the range of about 300-3600 mg/day, typically about900-2400 mg/day, more typically about 900-1800 mg/day.

An effective dosage of gabapentin for the treatment of neuropathic painis typically in the range of about 100-4800 mg/day, typically about300-3600 mg/day, more typically about 900-2400 mg/day.

An effective dosage of gabapentin for the treatment of psychiatricdisorders is typically in the range of about 100-4800 mg/day, moretypically about 900-3600 mg/day.

An effective dosage of gabapentin for the treatment of movementdisorders is typically in the range of about 100-4000 mg/day, typicallyabout 200-2700 mg/day, more typically about 500-2700 mg/day.

An effective dosage of gabapentin for the prophylactic treatment ofmigraine headaches is typically in the range of about 200-4000 mg/day,typically about 500-3600 mg/day, more typically about 900-2400 mg/day.

Dosage Regimen

The methods of the invention provide a once- or twice-daily dose of thegabapentin gastric retained dosage form. The dosage can be administeredat any time, but it is preferred that the dosage is administered at thesame approximate time each day and in approximately 12 hour intervalsfor the duration of treatment. In addition, it is preferred that thegastric retained dosage form be taken with food, for example with themorning or evening meals.

Accordingly, in one embodiment of the invention, gabapentin isadministered once-daily, for example, in the morning (e.g., upon risingor with the morning meal) or in the evening (e.g., with the evening mealor near bedtime).

In another embodiment of the invention, gabapentin is administeredtwice-daily, for example, with the first dose being in the morning(e.g., upon rising or with the morning meal) and the second dose beingin the evening (e.g., with the evening meal or near bedtime).

In another aspect of the invention, the method of administering atherapeutically effective amount of gabapentin in a gastric retaineddosage form further includes administering one or more additionaltherapeutic agents.

The additional therapeutic agents can be administered at the same timeor at a different time than the administration of gabapentin, and willdepend upon the nature of the disease being treated as well as the agentitself. For example, when the additional agent is anotheranti-epileptic, a twice-daily dose is sufficient and it may beadministered at the same time or at a different time than gabapentin.For purposes of facilitating patient compliance, administration of anyof the aforementioned additional agents at the same time is preferred.

Dosage Form

There are several drug delivery systems that are suitable for use indelivering gabapentin in the method of the invention as they areparticularly tailored to be gastric-retained dosages, such as theswellable bilayer described by Franz, et al., U.S. Pat. No. 5,232,704;the multi-layer tablet with a band described by Wong, et al., U.S. Pat.No. 6,120,803; the membrane sac and gas generating agent described inSinnreich, U.S. Pat. No. 4,996,058; the swellable, hydrophilic polymersystem described in Shell, et al., U.S. Pat. No. 5,972,389 and Shell, etal., WO 9855107; all of which are incorporated herein by reference.

Of particular interest are gastric retained dosage forms that containhydrophilic polymers that swell to a size such that the dosage form isretained in the fed mode. For example, the gastric retained dosage formcan contain polymers with a high swelling capacity such as polyethyleneoxide, hydroxyethylcellulose and hydroxypropylmethylcellulose. Thepolymers are preferably of a moderate to high molecular weight (4×10³ togreater that 10⁷) to enhance swelling and provide control of the releaseof gabapentin. In one embodiment of the invention, ahydroxypropylmethylcellulose polymer of such molecular weight isutilized so that the viscosity of a 1% aqueous solution is about 4000cps to greater than 100,000 cps. An example of suitable polyethyleneoxide polymers are those having molecular weights (viscosity average) onthe order of 2-7 million. A typical dosage form should swell toapproximately 115% of its original volume within one hour afteradministration, and at a later time should swell to a volume that is130% or more of the original volume. Fillers, binders, lubricants andother additives may also be included in the gastric retained dosageform, such as are well known to those of skill in the art.

A typical dosage form would provide for a drug delivery profile suchthat gabapentin both on an in vivo and in vitro basis, is delivered forat least 5 hours, and typically over a time period of about 8-10 hours.In order to provide for sustained delivery, it is preferable that atleast 40 wt % of gabapentin is retained in the dosage form after 1 hour,i.e., no more than 60 wt % of the drug is administered in the firsthour. In addition, it may be desired to utilize a dosage form thatprovides for substantially all of the gabapentin to be delivered overthe intended duration, which is typically about 6-12 hours, wheresubstantially all is taken to mean at least about 85 wt % of thegabapentin is administered.

In one embodiment of the invention, the gastric retained dosage form ofgabapentin is a capsule dosage form that allows for the extended releaseof gabapentin in the stomach and comprises: (a) at least one componentthat expands on contact with gastric juice and contains an agent capableof releasing carbon dioxide or nitrogen, gabapentin or apharmaceutically acceptable salt thereof; (b) at least one hydrophilicmembrane in the form of a sachet which contains component (a), expandsby inflation, floats on the aqueous phase in the stomach and ispermeable to gastric juice and; (c) capsule dosage form which containscomponents (a) and (b) and which disintegrates without delay in thestomach under the action of gastric juice. Component (a) may alsocontain a pharmaceutically acceptable hydrophilic swelling agent such aslower alkyl ethers of cellulose, starches, water-soluble aliphatic orcyclic poly-N-vinylamides, polyvinyl alcohols, polyacrylates,polymethacrylates, polyethylene glycols and mixtures thereof, as well asother materials used in the manufacture of pharmaceutical dosage forms.Further details regarding an example of this type of dosage form can befound in Sinnreich, U.S. Pat. No. 4,996,058.

In another embodiment of the invention, the gastric retained dosage formof gabapentin is an extended release oral drug dosage form for releasinggabapentin into the stomach, duodenum and small intestine of a patient,and comprises: a single or a plurality of solid particles consisting ofgabapentin or a pharmaceutically acceptable salt thereof dispersedwithin a polymer that (i) swells unrestrained dimensionally by imbibingwater from gastric fluid to increase the size of the particles topromote gastric retention in the stomach of the patient in which the fedmode has been induced; (ii) gradually the gabapentin diffuses or thepolymer erodes over a time period of hours, where the diffusion orerosion commences upon contact with the gastric fluid; and (iii)releases gabapentin to the stomach, duodenum and small intestine of thepatient, as a result of the diffusion or polymeric erosion at a ratecorresponding to the time period. Exemplary polymers includepolyethylene oxides, alkyl substituted cellulose materials andcombinations thereof, for example, high molecular weight polyethyleneoxides and high molecular weight or viscosityhydroxypropylmethylcellulose materials. Further details regarding anexample of this type of dosage form can be found in Shell, et al., U.S.Pat. No. 5,972,389 and Shell, et al., WO 9855107.

In yet another embodiment, a bi-layer tablet releases gabapentin to theupper gastrointestinal tract from an active containing layer, while theother layer is a swelling or floating layer. Details of this dosage maybe found in Franz, et al., U.S. Pat. No. 5,232,704. This dosage form maybe surrounded by a band of insoluble material as described by Wong, etal., U.S. Pat. No. 6,120,803.

Another embodiment of the invention uses a gastric retained swellable,sustained-release tablet having a matrix comprised of poly(ethyleneoxide) and hydroxypropylmethylcellulose. This dosage form is illustratedin Example 1 and further details may be found in Gusler, et al.,“Optimal Polymer Mixtures For Gastric Retentive Tablets,” filed on likedate herewith and identified as 10/029,134, the disclosure of which isincorporated herein by reference.

For those embodiments of the invention that include furtheradministering additional therapeutic agents simultaneously withgabapentin, these agents can either be administered in the gastricretained dosage form that includes gabapentin or can be administered ina dosage form that is separate from gabapentin. Exemplary dosage formsare described below.

Dosage Form of Additional Agents

For those embodiments of the invention that include furtheradministering one or more additional therapeutic agents, such dosagescan be any suitable formulation as are well known in the art. For thoseadditional agents where controlled release is desirable, the agent maybe incorporated in the gabapentin gastric retained dosage form or beadministered in a separate gastric retained or other controlled releaseformulation dosage form. For those additional agents where immediaterelease is desirable, the agent may be incorporated in a coating aroundthe gabapentin gastric retained dosage form or in a separate layer of abilayer tablet, the agent may be simply enclosed in the capsule of theaforementioned gabapentin gastric retained capsule dosage form, or theagent may be administered in a separate immediate release dosage form.

Typically, dosage forms contain the additional agent (anotheranti-epileptic or anticonvulsant agent) in combination with one or morepharmaceutically acceptable ingredients. The carrier may be in the formof a solid, semi-solid or liquid diluent, or a capsule. Usually theamount of active agent is about 0.1-95 wt %, more typically about 1-50wt %. Actual methods of preparing such dosage forms are known, or willbe apparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 18thEdition, 1990. The dosage form to be administered will, in any event,contain a quantity of the additional therapeutic agent(s) in an amounteffective to alleviate the symptoms of the subject being treated.

In the preparation of pharmaceutical formulations containing theadditional therapeutic agent in the form of dosage units for oraladministration the agent may be mixed with solid, powdered ingredients,such as lactose, microcrystalline cellulose, maltodextrin, saccharose,sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin,or another suitable ingredient, as well as with disintegrating agentsand lubricating agents such as magnesium stearate, calcium stearate,sodium stearyl fumarate and polyethylene glycol waxes. The mixture isthen processed into granules or pressed into tablets such as chewableand oral disintegrating tablets.

Soft gelatin capsules may be prepared by mixing the active agent andvegetable oil, fat, or other suitable vehicle. Hard gelatin capsules maycontain granules of the active agent, alone or in combination with solidpowdered ingredients such as lactose, saccharose, sorbitol, mannitol,potato starch, corn starch, amylopectin, cellulose derivatives orgelatin.

Liquid preparations for oral administration may be prepared in the formof syrups or suspensions, e.g. solutions or suspensions containing about0.2-20 wt % of the active agent and the remainder consisting of sugar orsugar alcohols and a mixture of ethanol, water, glycerol, propyleneglycol and polyethylene glycol. If desired, such liquid preparations maycontain coloring agents, flavoring agents, saccharin and carboxymethylcellulose or other thickening agents. Liquid preparations for oraladministration may also be prepared in the form of a dry powder to bereconstituted with a suitable solvent prior to use.

When the method of the invention includes administering anotheranti-epileptic or an anticonvulsant agent, there are numerouscommercially available dosage forms that can be administered. Inaddition, other formulations can be readily designed based uponknowledge in the art, and include the gastric-retained delivery systemsdescribed above.

Typical dosage forms of the other anti-epileptics or anticonvulsantssuitable for use in the invention include tablets, capsules, oralsuspensions and syrup. One of skill in the art can readily prepare oneof these exemplary formulations or the other anti-epileptic can beadministered by means of one of the numerous commercially availableproducts, examples of which are provided below.

Commercially available hydantoin anticonvulsants include, for example,Peganone® (ethotoin, Abbott); Mesantoin® (mephenytoin, Sandoz); andDilantin® (phenytoin, Warner-Lambert).

Typical dosage forms of the antineuralgics suitable for use in theinvention include tablets, capsules and oral suspensions. One of skillin the art can readily prepare one of these exemplary formulations orthe antineuralgic can be administered by means of one of the numerouscommercially available products, examples of which are provided below.

Commercially available antineuralgics include, for example, Atretol®(carbamazepine, Elan).

Although specific examples of suitable anti-epileptic, anticonvulsantagent and antineuralgic formulations are described above, it isunderstood that the invention is not limited to those examples as thereare numerous other formulations that can be used to deliver the otheranti-epileptic or anticonvulsant agents.

The general methods of the invention are best understood with referenceto the following examples which are intended to enable those skilled inthe art to more clearly understand and to practice the presentinvention. These examples are not intended, nor are they to beconstrued, as limiting the scope of the invention, but are merelyillustrative and representative thereof.

EXAMPLE 1

Tablets were manufactured using a dry blend process, and hand made on aCarver ‘Auto C’ Press (Fred Carver, Inc., Indiana). The dry blendprocess consisted of blending all of the ingredients in a plastic bag,and compressing into a 1000 mg tablet (600 mg gabapentin dose) using a0.7086″×0.3937″ Mod Oval die (Natoli Engineering). The parameters forthe operation of the Carver ‘Auto C’ Press were as follows: 4000 lbs.force, 0 second dwell time (the setting on the Carver Press), and 100%pump speed.

Formulation Composition (wt %) PEO Methocel Sample # Active CoagulantK100M M. St. 1 60.0 39.0 0.0 1 2 60.0 24.3 14.7 1 3 60.0 0.0 39.0 1where: Active = gabapentin PEO Coagulant = poly(ethylene oxide), gradePolyOx Coagulant, NF FP grade, manufactured by Union Carbide/DowChemical Company Methocel K100M = hydroxypropylmethylcellulose, gradeMethocel K100M, premium, manufactured by Dow Chemical Company M. St. =magnesium stearate, NF, supplied by Spectrum Chemical Company

The dissolution was determined in USP apparatus 1 (40 mesh baskets), 100rpm, in deionized water. Samples, 5 ml at each time-point, were takenwithout media replacement at 1, 4 and 8 hours.

The resulting cumulative dissolution profile, based upon a theoreticalpercent active added to the formulations is presented in tabulated formbelow:

Theoretical wt % of Active Released Time (hours) Sample 1 Sample 2Sample 3 1 15.4 14.8 18.6 4 39.4 37.4 43.3 8 61.7 57.8 64.7

EXAMPLE 2

Tablets were manufactured using a dry blend process, and hand made on aCarver ‘Auto C’ Press (Fred Carver, Inc., Indiana). The dry blendprocess consisted of blending all of the ingredients in a plastic bag,and compressing into a 600 mg tablet (300 mg gabapentin) using a0.6299″×0.3937″ Mod Oval die (Natoli Engineering). The parameters forthe operation of the Carver ‘Auto C’ Press were as follows: ˜2000-2500lbs. force, 0 second dwell time (the setting on the Carver Press), and100% pump speed.

Formulation Composition (wt %) PEO Methocel Sample # Active CoagulantK15M M. St. 4 50.0 24.5 24.50 1 where: Active = gabapentin PEO Coagulant= poly(ethylene oxide), grade PolyOx Coagulant, NF FP grade,manufactured by Union Carbide/Dow Chemical Company Methocel K15M =hydroxypropylmethylcellulose, grade Methocel K15M, premium, manufactureby Dow Chemical Company M. St. = magnesium stearate, NF, supplied bySpectrum Chemical Company

The dissolution was determined in USP apparatus 1 (40 mesh baskets), 100rpm, in deionized water. Samples, 5 ml at each time-point, were takenwithout media replacement at 1, 2, 4 and 8 hours. The resultingcumulative dissolution profile, based upon a theoretical percent activeadded to the formulation is presented in tabulated form below:

Theoretical wt % of Active Released Time (hours) Sample A 1 20.6 2 32.44 49.7 6 63.1 8 74.0 10 82.6

EXAMPLE 3

Three Gstric Retentive (GR™) gabapentin formulas were manufacturedutilizing a standard granulation technique. The formulationsmanufactured are shown in tabulated form below.

Formulation for Clinical Trial Manufacture Gabapentin GR8, 300-Gabapentin GR6, 300- Gabapentin GR8, 600- mg (GR8, 300-mg) mg (GR6,300-mg) mg (GR8, 600-mg) 44.76% Gabapentin 44.76% Gabapentin 61.11%Gabapentin 21.99% Methocel ® 16.46% Methocel ®  7.59% Methocel ® K15M,premium K4M, premium K15M, premium 21.99% Sentry ® 21.99% Sentry ®27.09% Sentry ® PolyOx ® WSR PolyOx ® WSR 303, PolyOx ® WSR 303,Coagulant, NF FP NF FP NF FP  7.49% Avicel ® 12.98% Avicel ® PH-  0.00%Avicel ® PH- PH-101, NF 101, NF 101, NF  2.75% Methocel ®  2.75%Methocel ® E5,  3.22% Methocel ® E5, prem. prem. E5, prem.  1.00%Magnesium  1.00% Magnesium  1.00% Magnesium Stearate, NF Stearate, NFStearate, NF 670-mg (Tablet 670-mg (Tablet weight) 982-mg (Tabletweight) weight) 0.3937″ × 0.6299″ 0.3937″ × 0.6299″ 0.4062″ × 0.75″ ModOval Mod Oval Mod Cap

Gabapentin was obtained from Plantex U.S.A. (Englewood Cliffs, N.J.).Methocel® brand hydroxypropyl methylcellulose (also known ashypromellose), and Sentry® PolyOx® brand polyethylene oxide wereobtained from Dow Chemical (Midland, Mich.). Methocel E5, premium is aUSP type 2910 hydroxypropyl methylcellulose with number averagemolecular weight of on the order of 6000-8000 and a viscosity of 5 cpsas a 2% aqueous solution at 20 C. Methocel® K4M and Methocel® K15M areUSP type 2208 hydroxypropyl methylcellulose with viscosities of 4000 cpsand 15,000 cps, respectively, as a 2% aqueous solution at 20 C, andnumber average molecular weights on the order of 80,000 and 100,000,respectively. Sentry PolyOx® WSR 301, NF FP, Sentry® PolyOx® WSRCoagulant, NF FP and Sentry® PolyOx® WSR 303, NF FP haveviscosity-average molecular weights of approximately 4,000,000,5,000,000 and 7,000,000, respectively. Avicel PH-101, NF ismicrocrystalline cellulose supplied by FMC Corporation (Philadelphia,Pa.). Magnesium stearate, NF was supplied by Spectrum Quality Products(New Brunswick, N.J.).

The dissolution profiles, as determined by USP Apparatus I (100 rpm) inmodified simulated gastric fluid, for three prototypes GR™ formulationsare shown in FIG. 1.

EXAMPLE 4

The pharmacokinetic profiles of the three formulations described inExample 3, administered as a 600-mg dose, were compared to Neurontin®immediate release 300-mg capsule in a randomized four-way cross-overexperiment involving 15 healthy volunteers. Each subject wasadministered treatment of 600-mg gabapentin as one of the three GR™formulations (1×600-mg tablet or 2×300-mg tablet) or Neurontin® capsules(2×300-mg) within 5 minutes of completing a high fat breakfast (FDAbreakfast). Plasma samples were taken up to 48 hours post-dose. FIG. 2illustrates the average plasma profile for the four treatmentsadministered, and the pharmacokinetic data are summarized in tabulatedform below.

Gabapentin Plasma Data - Average for 15 Subjects AUC_(inf) ^(#) C_(max)^(#) Dosing ((ug/ml)*hr) (ug/ml) T_(max) (hours) Neurontin ®, 300-mgMean: 46.65 4.72 3.93 2 × capsules % CV: 19.0 20.2 15.1 GR6, 300-mgMean: 44.43 2.97 6.63 2 × tablets % CV: 34.9 29.7 45.1 GR8, 300-mg Mean:41.84 3.10 5.63 2 × tablets % CV: 34.4 26.2 34.9 GR8, 600-mg Mean: 48.013.13 7.13 1 × tablet % CV: 26.8 18.7 42.2 ^(#)Geometric Mean andGeometric % CV are reported here

As demonstrated in FIG. 2 and in tabulated form above, GR™ formulationsdemonstrate sustained release with a lower maximum plasma concentrationand a larger value for the time of the maximum concentration compared tothe immediate release capsules without loss in the bioavailability asmeasured by the plasma AUC_(inf).

Each of the patent applications, patents, publications, and otherpublished documents mentioned or referred to in this specification isherein incorporated by reference in its entirety, to the same extent asif each individual patent application, patent, publication, and otherpublished document was specifically and individually indicated to beincorporated by reference.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1. A method of treating epilepsy in a mammal comprising administering atherapeutically effective amount of a daily dosage of about 200 mg toabout 4000 mg of gabapentin or a pharmaceutically acceptable saltthereof, dispersed in a gastric retained dosage form to the mammal inwhich a fed mode has been induced, wherein the dosage form comprises asingle polymer matrix comprising at least one swellable hydrophilicpolymer that swells in a dimensionally unrestrained manner by imbibingwater to increase its size to promote gastric retention of the dosageform in the stomach of the mammal, and wherein upon contact with water,gabapentin is released by diffusion from the dosage form over a periodof at least five hours and at least 40 wt % of the gabapentin isretained in the dosage form one hour after administration.
 2. The methodof claim 1 wherein the dosage form is administered once-daily.
 3. Themethod of claim 2 wherein the dosage form is administered with a meal.4. The method of claim 1 wherein the dosage form is administeredtwice-daily.
 5. The method of claim 4 wherein each dosage form isadministered with a meal.
 6. The method of claim 1 which furthercomprises administering one or more additional anti-epileptics oranticonvulsants.
 7. The method of claim 1 wherein the daily dosage isabout 600-2700 mg.
 8. The method of claim 1 wherein the daily dosage isabout 900-1800 mg.
 9. The method of claim 1 wherein the gastric retaineddosage form releases gabapentin into the stomach, duodenum and smallintestine.
 10. The method of claim 1 wherein the dosage form providesadministration of at least 80 wt % of the gabapentin to be deliveredover a period of about 5-12 hours.
 11. The method of claim 1, whereinthe hydrophilic polymer is selected from the group consisting ofpolyethylene oxides, alkyl substituted cellulose materials, andcombinations thereof.
 12. The method of claim 1 wherein the dosage formfurther comprises a gas generating agent.
 13. The method of claim 12wherein the gabapentin is contained in a membrane sachet with the gasgenerating agent.
 14. The method of claim 1 wherein the dosage form is abilayered or multilayered adhesive tablet.
 15. The method of claim 1wherein the gastric retained dosage form is a capsule dosage form formthat release gabapentin in the stomach,duodenum and small intestine. 16.The method of claim 1 wherein the gastric retained dosage form is atablet and the matrix is comprised of poly(ethylene oxide) andhydroxypropylmethylcellulose.
 17. A method of treating neuropathic painin a mammal comprising administering a therapeutically effective amountof a daily dosage of about 100 mg to about 4800 mg of gabapentin or apharmaceutically acceptable salt thereof, dispersed in a gastricretained dosage form to the mammal in which a fed mode has been induced,wherein the dosage form comprises a single polymer matrix comprising atleast one swellable hydrophilic polymer that swells in a dimensionallyunrestrained manner by imbibing water to increase its size to promotegastric retention of the dosage form in the stomach of the mammal, andwherein upon contact with water, gabapentin is released by diffusionfrom the dosage form over a period of at least five hours and at least40 wt% of the gabapentin is retained in the dosage form one hour afteradministration.
 18. The method of claim 17 wherein the dosage form isadministered once-daily.
 19. The method of claim 18 wherein the dosageform is administered with a meal.
 20. The method of claim 17 wherein thedosage form is administered twice-daily.
 21. The method of claim 20wherein each dosage form is administered with a meal.
 22. The method ofclaim 17 further comprising administering one or more therapeutic agentsselected from the group consisting of anticonvulsants, tricyclicantidepressants, opioids, and levodopa.
 23. The method of claim 17wherein the daily dosage is about 300-3600 mg.
 24. The method of claim17 wherein the daily dosage is about 900-2400 mg.
 25. The method ofclaim 17 wherein the gastric retained dosage form releases gabapentin tothe stomach, duodenum and small intestine.
 26. The method of claim 17wherein the dosage form provides administration of at least 85 wt % ofthe gabapentin to be delivered over a period of about 5-12 hours. 27.The method of claim 1 wherein the hydrophilic polymer is selected fromthe group consisting of polyethylene oxides, alkyl substituted cellulosematerials, and combinations thereof.
 28. The method of claim 1 whereinthe dosage form further comprises a gas generating agent.
 29. The methodof claim 28 wherein the gabapentin is contained in a membrane sachetwith the gas generating agent.
 30. The method of claim 17 wherein thedosage form is a bilayered or multilayered adhesive tablet.
 31. Themethod of claim 17 wherein the dosage form is a capsule dosage form thatreleases gabapentin in the stomach duodenum and small intestine.
 32. Themethod of claim 17 wherein the gastric retained dosage form is a tabletand the matrix is comprised of poly(ethylene oxide) andhydroxypropylmethylcellulose.
 33. A method of administering atherapeutically effective amount of a daily dosage of about 100 mg toabout 4800 mg of gabapentin to a mammal, comprising administeringgabapentin or a pharmaceutically acceptable salt thereof, dispersed in agastric retained dosage form to the mammal in which a fed mode has beeninduced and wherein the dosage form comprises a single polymer matrixcomprising at least one swellable hydrophilic polymer that swells in adimensionally unrestrained manner by imbibing water to increase its sizeto promote gastric retention of the dosage form in the stomach of themammal, and wherein upon contact with water, gabapentin is released bydiffusion from the dosage form over a period of at least five hours andat least 40 wt % of the gabapentin is retained in the dosage form onehour after administration.
 34. The method of claim 33 wherein the dosageform is administered once-daily.
 35. The method of claim 34 wherein thedosage form is administered with a meal.
 36. The method of claim 33wherein the dosage form is administered twice-daily.
 37. The method ofclaim 36 wherein each dosage form is administered with a meal.
 38. Themethod of claim 33 where the administering is to a mammal diagnosed withor suffering from epilepsy.
 39. The method of claim 33 where theadministering is to a mammal diagnosed with or suffering fromneuropathic pain.
 40. The method of claim 33 wherein the gastricretained dosage form releases gabapentin to the stomach, duodenum andsmall intestine.
 41. The method of claim 33 wherein the dosage formprovides administration of at least 80 wt % of the gabapentin to bedelivered over a period of about 5-12 hours.
 42. The method of claim 33wherein the hydrophilic polymer is selected from the group consisting ofpolyethylene oxides, alkyl substituted cellulose materials, andcombinations thereof.
 43. The method of claim 33 wherein the dosage formfurther comprises a gas generating agent.
 44. The method of claim 43wherein the gabapentin is contained in a membrane sachet with the gasgenerating agent.
 45. The method of claim 33 wherein the dosage form isa bilayered or multilayered adhesive tablet.
 46. The method of claim 33wherein the dosage form is a capsule dosage form that releasesgabapentin in the stomach, duodenum and small intestine.
 47. The methodof claim 33 wherein the gastric retained dosage form is a tablet and thematrix is comprised of poly (ethylene oxide) andhydroxypropylmethylcellulose.
 48. The method of claim 1, wherein thehydrophilic polymer swells to approximately 115% of its original volumewithin one hour of administration.
 49. The method of claim 17, whereinthe hydrophilic polymer swells to approximately 115% of its originalvolume within one hour of administration.
 50. The method of claim 33,wherein the hydrophilic polymer swells to approximately 115% of itsoriginal volume within one hour of administration.
 51. The method ofclaim 1, wherein the administering achieves a reduced incidence of sideeffects to the central nervous system, relative to a non-gastricretained dosage form.
 52. The method of claim 17, wherein theadministering achieves a reduced incidence of side effects to thecentral nervous system, relative to a non-gastric retained dosage form.53. The method of claim 33, wherein the administering achieves a reducedincidence of side effects to the central nervous system, relative to anon-gastric retained dosage form.
 54. The method of claim 1, wherein thehydrophilic polymer has a molecular weight of about 4×10³ to about1×10⁷.
 55. The method of claim 17, wherein the hydrophilic polymer has amolecular weight of about 4×10³ to about 1×10⁷.
 56. The method of claim33, wherein the hydrophilic polymer has a molecular weight of about4×10³ to about 1×10⁷.
 57. The method of claim 16, wherein the poly(ethylene oxide) has a molecular weight of about 2,000,000 daltons toabout 7,000,000 daltons.
 58. The method of claim 16, wherein thehydroxypropylmethylcellulose has a viscosity of about 4000 cps to about100,000 cps as measured in a 1% aqueous solution.
 59. The method ofclaim 41, wherein the hydroxypropylmethylcellulose has a viscosity ofabout 4000 cps to about 100,000 cps as measured in a 1% aqueoussolution.
 60. The method of claim 1, wherein the mammal is a human. 61.The method of claim 17, wherein the mammal is a human.
 62. The method ofclaim 33, wherein the mammal is a human.
 63. The method of claim 33,wherein the total amount of gabapentin in the daily dosage is about300-3600 mg.
 64. The method of claim 33, wherein the total amount ofgabapentin in the daily dosage is about 900-2400 mg.
 65. The method ofclaim 1, wherein the dosage form is a bilayered tablet.
 66. The methodof claim 17, wherein the dosage form is a bilayered tablet.
 67. Themethod of claim 33, wherein the dosage form is a bilayered tablet.